Current therapeutic interventions for treating cancerous conditions focus on inhibiting cancer cell propagation by killing, extracting or retarding their growth. The role of mitochondria in promoting cell death has drawn much attention as a potential target for the next generation of anti-cancer agents. Mitochondria are a key regulatory node for the stress-activated intrinsic programmed cell death (PCD). Mitochondria are dynamic organelles undergoing constant fusion and fission during normal cell division. The equilibrium between fission and fusion is controlled by the activity of conserved molecular machines driven by dynamin-like GTPases (Westermann, 2010). In response to cytotoxic damage, the mitochondria may undergo extensive fission accompanied by mitochondrial outer membrane permeability (MOMP) which releases sequestered pro-apoptotic proteins into the cytoplasm. In budding yeast, mitochondrial fission requires the GTPase Dnm1p that forms atypical helical filaments that first encircle, then constrict, mitochondria until scission is achieved (Mears et al., 2011). Recruitment of Dnm1p to the mitochondria requires the outer membrane protein Fis1p (Mozdy et al., 2000; Tieu et al., 2002) and one of two adaptor proteins, Mdv1p (Mozdy et al., 2000; Tieu and Nunnari, 2000) or Caf4p (Griffin et al., 2005). On the other side of the equation, the fusion of the inner and outer mitochondrial membranes requires the Mgm1p and Fzo1p GTPases, respectively (Meeusen et al., 2006; Rapaport et al., 1998). Several studies have demonstrated that the proper balance of fission and fusion is required for normal mitochondrial function (Ishihara et al., 2009; Wakabayashi et al., 2009).
The balance between fission and fusion is shifted dramatically toward fission in cells exposed to exogenous stress (Westermann, 2010). Mitochondrial hyper-fission is a conserved hallmark of the stress response (Igaki et al., 2000; Karbowski et al., 2002; Vieira et al., 2002) and is associated with the release of sequestered programmed cell death (PCD) inducing factors from this organelle (Breckenridge et al., 2003; Frank et al., 2001).
At least one underlying mechanism allowing tumor progression and resistance to anti-cancer therapies is the ability of cancerous cells to inhibit the intrinsic PCD pathway. For example, overexpression of the B Cell lymphocyte 2 (Bcl-2) pro-survival BH3 protein prevents MOMP. Such overexpression is observed in a high percentage of chronic lymphocytic leukemia (CLL) patients. However, efforts to design therapies that inactivate pro-survival proteins or stimulate pro-death components have been hampered due to a fundamental lack of understanding about how other pathways impinge on mitochondrial function and PCD induction. As such there is a need in the art to further identify the correlation among various components that activate or deactivate the cell death system in patients suffering from cancer and thereby improve or supplement available methods of treatment in the fight against cancer. Such knowledge can further lead to discovery of new therapeutic compositions and methods of applying or administering the same to treat hyperplasia or cancerous conditions in subjects in need of such treatment.